Antiseptic acridane compounds



Patented July 14, 1953 ANTISEPTIC ACRIDANE COMPOUNDS,

Donalee L. Tabern, Lake Bluff, Ill., assignor to Abbott Laboratories,North Chicago, Ill., a corporation of Illinois N Drawing. ApplicationOctober 19, 1948,

Serial No. 55,424

This invention relates in general to acridine compounds and morespecifically to substituted acridine compounds of thefollowingstructure, which are more properly called acridanes:

wherein R is an alkyl group containing from one to fourteen carbon atomsinclusive; X is a monovalent radical selected from class comprisinghydrogen, halogen, alkyl and alkoxy groups; Y is a hydrocarbon groupcontaining from one to ten carbon atoms inclusive and Z is a mineralacid anion. Other useful compounds of the present invention have alsobeen prepared in which Z is an alkoxy group (the alkyl group of whichcontains from one to four carbon atoms inclusive), or a hydroxyl group.

The OR group in the above formula may be in any position: ortho, meta orpara. For ease in preparation the para compound is often preferred.

It has long been known that various of the acridines have served asantiseptics and germicides. Among the most important of these areproflavine and acrifiavine.

The acridines are characterized by a heterocyclic central ringcontaining one nitrogen atom as indicated in the structural formulabelow:

28 Claims. ((1167-65) the Q-carbon, compounds are obtained, which, whenconverted to suitable salts, such as the halide or sulfate, have uniquephysiological prope erties. These compounds are usually light yellow toorange in color. They are soluble in Water or in the usual tincturemenstra at pH ranges of 3 to 7. These solutions are stable to light andair; remaining unchanged for many months. In the concentrations requiredfor sterilization of the skin or mucous surfaces, they cause littleirritation. These compounds penetrate the skin facilitate the isolationand purification of the reaction products.

-The' water-soluble acridane salts are active against a wide variety oforganisms both gram positive and gram negative and even against certainpathogenic fungi. Their antiseptic activity persists to a great extenteven in the presence of such organic matter as gelatine, sputum andsera. As little as 1 milligram of the compounds of this invention percc. of saliva acts as an antacid in the mouth which is so important inthe prevention of tooth decay. Moreover, most of these compounds areonly moderately bitter, and in view of the above stated properties arevaluable in treating infections of the throat and mouth.

An increase in the size of the alkyl group of the alkoxy-phenylsubstituent from methoxy to n-hexoxy increases the antiseptic power manyfold even when in dilutions of 1 to 5,000,000 for the latter compounds.Investigations also indicate that as the size of this chain isincreased, the surface tension of the aqueous solutions decreases,giving increased drug penetration. The alkoxy group may be on anyposition of the phenyl ring: ortho, meta or para. From the standpoint ofease of preparation, the p-alkoxy phenyl compounds are preferred.

The hydrocarbon group Y may be an alkyl, aryl or aralkyl groupcontaining one to ten carbon atoms inclusive. For ease of manufacture 3and economy, the groups are preferably methyl, ethyl, phenyl, or benzyl.The compounds of the invention may be further substituted in theacridine rings. Also one of these rings may be saturated orheterocyclic.

The processes of synthesizing the substituted anthranilic acids andsimple acridones used as intermediates are in general those of theliterature. Acridones are characterized by the following structure:

7 ing bomb at 130-140 C. for four hours.

product N-hexyl acridone is isolated as in Exam- For example, acridonemay be prepared from phenylanthranilic acid by ring closure withsulfuric acid or with phosphorous pentichloride plus aluminum chloride.

For the preparation of substituted N-alkyl, or aralkyl acridones theprocesses of the prior art have been found less saisfactory than thosethat I have discovered. These latter processes are described below:

Process (A) 'O ample below:

EXAMPLE IA About 10 gms. of acridone and gms. of sodium hydroxide aredissolved in alcohol with stirring and heating. Most of the solvent isthen distilled off and replaced by a hydrocarbon solvent such as xyleneand preferably a solvent boiling between 100 and 150 C. To this solutionis added 10 to 15 "gms. of dimethyl sulfate dissolved in dry acetone andthe mixture warmed. On cooling the resulting methyl acridoneprecipitates. The precipitate is then filtered and purified. bycrystallization. The yield from this process is from 85-90% of thetheoretical.

An alternative process for the preparation of N-alkyl acridones reactsan alkali-metal alcoholate with the acridone to form the alkali-metalsalt of the acridone. This product is reacted with an alkyl halide toform the N-alkyl acridone.

This reaction may be illustrated by the following illustration:

+ VROM N/ i l 0 V o l t (I RlX N N it 1's 4 wherein M is an alkalimetal, R is an alkyl group, R is an alkyl or aralkyl group and X may bechlorine, bromine or iodine. A specific example to illustrate thisprocess is given below.

EXAMPLE IB About 15 gms. of potassium metal is dissolved in an excess ofmethyl alcohol. To this solution is added about 50 gms. of acridone andthe excess alcohol is removed by distilling with xylene. Hexyl'chloride'irithe amount of 125 gms. is added to the mixture and thewhole heated in a rock- The ple IA and purified by recrystallizationfrom alcohol.

' EXAMPLE IC Iiia manner similar to that of Example IB, N benzylacridone may be prepared by reacting 'gm's. of the potassium salt ofacridone with 2 moles ofbenzyl chloride at -140" C. for nine hours togive 9 gms. of product melting at 181 C.

N-aryl acridones are best prepared from the appropriate triphenylaminecarboxylic acids by ring closure.

By the use of the above procedures the N-substituted acridones used asintermediates may be prepared.

Neither do the processes reported in the literature for the preparationof compounds similar to the acridanes of the invention work well. Theseprocesses teachusing the Grignard reagent and the result of the processis the formation of an insoluble Grignard complex which will not reactfurther. I have discovered anew process for making9-a1koxy-phenyl-10-hydrocarbon substituted acridine derivatives whichmay be outlined as follows: A halo (such as iodo)-aryl-alkoxy compound(I) is reacted with an alkali metal such as lithium in an inert solventsuch as ether to form the lithium derivative (II). The lithiumderivative reacts rapidly with the N-substituted acridone (III) (seeExamples IA, IE, 10) to give the essentially pure acridol (IV) inpractically quantitative yields. The reaction product remains'dissolvedin the solvent. Addition of gaseous hydrogen halides gives the etherinsoluble halide (V) or halo-hydrochloride (VI) which are lemon yellowpowders which may be removed by filtration. When the halo-hydrohalide isdissolved in an inert solvent such as chloroform and a neutralizingagent such as dry calcium carbonate is added, which removes the excessacid, a neutral halide acridane (VII) is obtained which is very solublein water and alcohol. This latter product may also be obtained'by dryingthe'halohydrohalide with heat.

Some of the mineral-acid anion acridones are diflicult to purify.Therefore, for purification or characterization it maybe convenient toisolate the crude acridols (IV and VIII) by addition of excess alkali tothe solution of the halide (V) in water. These acridols upon warmingwith an alkanol such as methanol give colorless and usually crystallinemethoxyl derivatives (IX). The addition of an excess of hydrogen halidewill reconvert the methyl ether to the halide (V). Sulfuric acid may beused in this synthesis in place of the hydrogen halide to form thebisulfate. This process may be illustrated by the following reactionswith the compounds numbered to conform to the description above:

OR OR I g a L1 I v I a I (1) Li (H) Y (III) OR OR O 20 HZ X y I X N E:III X (IV) Y (V) OR OR zz (I 11 CaCOg alkali X orheat AK f H Y 2 (VI) Y(VII) OR OR OH 00113 I/ I/ C C CHZlOH t Y (VIII) Y (IX) wherein R is analkyl group containing from one to fourteen carbon atoms inclusive; X isa monovalent radical selected from the class comprising hydrogen,halogen, alkyl and alkoxy groups; Y is a hydrocarbon group containingone to ten carbon atom inclusive; Z is a mineral acid anion such aschlorine, bromine, iodine and sulfate.

In the formulae above it is understood that the aromatic rings may besuitably substituted.

It is possible to write several tautomeric formulae for the productswhich are the subject of this invention. The ethers are, as has beenstated, colorless and possess the structure:

6' By analogy the halide and sulfate derivatives would possess thestructure:

These derivatives, on the other hand, are deeply colored. It was shownmany years ago [Journal American Chemical Society 48, 1345 (1926)] thatin the case of certain related compounds, these derivatives may form bya simultaneous tautomerization to a quinonoid form, expressable in thiscase as On the other hand, by convention, proflavine i written ascontaining a pentavalent nitrogen and by analogy these compounds couldbe represented by Quite obviously, the exact mode of expressing thestructure here under discussion is immaterial and for purposes ofgeneralization the formulation Many of these compounds possess quiteunexpected physica1 properties. For instance, the

EXAMPLE II 9- (p-n-hexoxyphenyll -10-methyl acridane chloride CsH2a Toapproximately 1.4 gms. of lithium suspended in 100 cc. of anhydrousether is added drop-wise about gms. of p-(n-hexoxy) -phenyl iodide atsuch a rate that the surface of the metal remains bright. When thereaction ceases, as evidenced by the solution of the lithium metal, anamount of from. 19 to 21 gms. of powdered, dry N-methyl acridone isadded gradually. This reaction mixture is refluxed for 2 or 3 hoursfollowing which ice wateriis added alongwith sufficientzdiethyl ether.to: dissolve theorganic matter present. The ether solution is separated,washed with water, dried and treated with gaseous hydrogen chloride. Theinsoluble chloride hydrochloride is thus formed which is separated byfiltration and recrystallized from toluene. The chloride hydrochloridemay be converted to the chloride either by drying the compound withheatorby dissolving the chloride hydrochloride in'*'chloroform andtreating this solution with dried calcium carbonate. If the latterprocedure is used the excess calcium carbonate and calcium stains theskin to a clear yellow color which color is readily. removed by washingwith soap and water.

EXAMPLE III 9- (p-n-hexoatyphenyl) -10-methyl acridome bisulfate Toapproximately 1.5 grams of lithium metal The compound is readily ni -200cc. of anhydrous ether which has been heated to reflux is added 25.7grams of p-bromophenyl-n-hexyl ether, with stirring over a period ofabout one hour. After further stirring and refluxing, the mixture iscooled somewhat and 20.9 grams of N-methyl acridone is added over aperiod of about 10 minutes. After a short period of further stirring andrefluxing, the solution is cooled, filtered and poured into 250 cc. ofice and water.- The ether solution and the water solution separate intotwo phases. The aqueous phase is-extracted with cc. of ether. This etherextract is combined with the ether phase, washed twice with water anddried over anhydrous magnesium sulfate. The light orange coloredsolution is filtered, treated with adsorbing charcoal and refiltered.The filtrate is orangeyellow in color. The ethereal solution contains 9-(p-n-hexoxyphenyl) -10-methyl-9-acridol.

One half of the above solution containing the carbinol is diluted into150 cc. with anhydrous ether. To this solution is added dropwise asolution of 5.16 grams of sulfuric acid dissolved in 50 cc. of etheruntil the precipitation of the orange-yellow bisulfate is complete. Thisrequires about one half of the ethereal sulfuric acid solution. Thisprecipitate is removed by filtration, washed twice with ether and twicewith nhexane and dried in vacuum at 50 C.

The crude bisulfate form is purified as follows:

About 7.0 grams of crude sulfate obtained above is dissolved in aboutcc. of toluene and about 10 cc. of absolute ethanol, at the boilingpoint of the solvent. The solution is concentrated by distilling offmost of the alcohol. Toluene is added and most of the remainder of theethanol distilled off. On seeding with the crude bisulfate, the pureproduct begins to crystallize from the solution. After the solution hasbeen cooled the bisulfate is filtered, washed with toluene and dried at50 C. in vacuum. The yellowish-orange platelets of 9 (p n hexoxyphenyl)10 methyl acridane bisulfate melt at 229-230.5 C. with decomposition.The product analyzes for the bisulfate rather than the sulfate.

EXAMPLE IV 9- (p-n-beroxyphenyl) -1 O-mefhyl acrzdanebromide To one halfof the ether solution of the 9-(pn hexoxyphenyl) -l0methyl-9-acridolprepared according to Example III, is added enough anhydrous ether todilute the solution to cc.

To this solution is added dropwise a solution of i 4.5 grams of hydrogenbromide gas dissolved in 50 cc. of anhydrous ether until precipitationof the yellowish-orange product is complete. Ap-

proximately one half of the above ethereal hydrogen bromide is needed.The crude bromide 9. form is filtered, washed three times with n-hexaneand dried in vacuum at 50 C.

About 7.0 grams of the crude bromide is dissolved in 100 cc. of boilingtoluene. The solution is concentrated until the product begins tocrystallize from the boiling solution. The solution is cooled, the solidremoved by filtration, washed with toluene and dried at 50 C. in vacuum.This procedure is repeated and a further purification accomplished by athird recrystallization from toluene which contains slightly over 1%absolute ethanol. The crystals are filtered, washed with toluene anddried at 50 C. in vacuum. The yellow plates of Q-(p-n-hexoxyphenyl)-10-methyl acridane bromide melts at 178-178.5 C. with decomposiiton.

EXAMPLE V 9- (p-methoxyphenyl) -1 O-phenyl acridane chloride In the samemanner as in Example III, pbromoanisole and lithium are reacted to giveplithium anisole. The p-lithium anisole is reacted With N-methylacridone to produce the lithium-salt ofQ-(p-methoxyphenyl)-10-pheny1-9-acridol.

This compound may be converted directly into the compound 9-(pmethoxyphenyl) -l-phenyl acridane chloride by filtering the driedethereal solution of the lithium salt of the acridol and precipitatingwith ethereal hydrogen chloride. The crude product is filtered, Washedwith nhexane aand dried at 50 C. in vacuum. The crude product ispurified by dissolving in ethyl acetate containing a small amount ofabsolute ethanol, treating with adsorbing charcoal, filtered,concentrated and cooled. The orange crystals formed are filtered, washedwith ethyl acetate and dried at 50 C. in vacuum. The orange, finelycrystalline Q-(p-methoxyphenyD- -phenyl acridane 'chloride melts at172.5- l'74.5 C. a

EXAMPLE VI 9-(o-methoxyphenyl) -10-jmethyl acridane chloride 1 In amanner analogous to that of Example V but using o-bromo anisole toprepare the o-lithium anisole and reacting this with N-methyl acridonethe crude compound 9-(o-methoxyphenyl) IO-methyl acridane chloride maybe prepared. The crude product may be purified as in Example IV byrecrystallizing from toluene containing a small amount of absoluteethanol. After repeating the crystallization several times in toluenecontaining the small amount of absolute ethanol, the product isrecrystallized from ethyl acetate containing a trace of ethanol. Thecompound Q-(o-methoxy-phenyl) 10 methyl acridane chloride is in the formof small, dense yellow crystals having a melting point of 208.5 to 209C. with decomposition.

EXAMPLE VII Q-(p-n-butoxyphenyl) -10-methyl acridane chloride In amanner analogous to that of Example IV reacting lithium metal withp-bromophenyl-nbutyl ether to form the p-lithium compound and reactingthis compound with N-methyl acridone, the above mentioned compound maybe prepared. After recrystallizing from toluene containing a smallamount of absolute ethanol, the compound 9-(p-n-butoxyphenyl) -10-methylacridane chloride is obtained in the form of small brownishyellow plateswhich have a melting point of 186.5- 187 C.

EXAMPLE VIII 9- (p-hexomyphenyl) -10-ethyl acridane chloride In a manneranalogous to that of Example II but using n-ethyl acridane withp-lithium phenyln-hexyl ether, the above mentioned compound may beprepared. After recrystallization from toluene containing a small amountof absolute ethanol, the compound 9-(p-hexoxyphenyl) -10- ethylacridanechloride thus prepared is in, a form of a light yellow powder having amelting point of 197.5'199.C. withdecomposition.

EXAMPLE IX 9- (p-n-hexoxyphenyl) -1 O-benzyl acridane chloride ({laHraIn a manner analogous to Example II but using N-benzyl acridone withp-lithium phenyl-n-hexyl ether, the above mentioned compound may beprepared. After recrystallization from toluene containing absoluteethanol the compound 9-(pn-hexoxyphenyl)-10-benzy1 acridane chloride isobtained in the form of orange-yellow crystals having a melting point of91-98 C. The compound is hygroscopic and difficult to obtain in pureform.

EXAMPLE X 9-(0ctoxyphenyl) -10-methyl acridane chloride CsH11ncomposition.

EXAMPLE XI 9- (p-Z-ethylbutoncyphenyl) -10--methyl acridane chloride(|JH1(I]HCzH c2115 (lib In a manner analogous to that of Example II butusing p-lithium phenyl-Z-ethylbutyl ether with N-methyl acridone, theabove mentioned compound may be prepared. After crystallization fromtoluene, the compound 9-(p-2-ethylbutoxyphenyl) --methy1 acridane chlorde is, O

12 tained in the form of yellow needles with a melting point of 157158C. with decomposition.

EXAMPLE XII 9-(p-rL-decyl0xyphenyl) -10-meihyl acridane chloride Giu a-(iii) In a manner analogous to that of Example II but using p-lithiumphenyl-n-decyl ether and N-methyl acridene the above mentioned compoundmay be prepared. After crystallization from toluene the compoundQ-(p-n-decyloxyphenyl) -10-methyl acridane chloride is obtained in theform of golden yellow needles having a melting point of 161-164 C. withdecomposition.

EXAMPLE XIII Z-methoxy-Q- (p-n-hezcoxyphenyl) -1 O-methyl acridanechloride SJsHxs- O I G 1 @OCEH i CH In a manner analogous to that ofExample II but using p-lithium phenyl-n-hexyl ether and2-methoxy-10-methyl acridone, the above mentioned compound may beprepared. After crystallization from toluene containing a small amountof absolute ethanol the compound 2- methoxy-9- (p-n-hexoxyphenyl)-10-methyl acridane chloride is obtained in the form of bright orangecrystals having a melting point of 196.5- 197C. with decomposition.

EXAMPLE XIV 1-chZor0-9- (p-n-hexoxyphenyl) -4,1 O-dimethyl acridanechloride (|JaH1sn CH3 CH3 In a manner analogous to that of Example IIbut using p-lithium phenyl-n-hexyl ether with 1-chloro-4,10-dimethylacridone, the above mentioned compound may be prepared. Aftercrystallization from ethyl acetate containing a small amount of absoluteethanol a compound 1- chloro 9 (p n-hexoxyphenyl) -4,10-dimethylacridane chloride is obtained as brilliant orangered platelets having amelting point of 98-102 C. with decomposition. q

. In a manner analogous to that of Example II the above mentionedcompound may be prepared by reacting p-lithium phenyl-n-tetradecyletherand N-methyl acridone. The compound may be purified in the previousexamples.

EXAMPLE XVI 9- (p-n-methoxyphenyl) -1 O-n-decyl acridane chloride 7 Inaccordance with the process of Example II the above mentioned compoundmay be prepared by reacting p-lithium phenyl-methyl ether with N-n-decylacridane. The compound may be purifled in the same manner as in theprevious examples. v

The alkyl groups of the Q-alkoxyphenyl substituent may be in cyclicform. For example, by starting with a p-cyclohexyloxyphenyl halide andreacting the lithium salt with N-methyl acridone, the compound producedis Q-(p-cyclohxyloxyphenyD-lO-methyl acridane chloride. In. addition tohaving the alkoxy group in the para and ortho positions the groupmay'be'in the meta position. For example, by starting with the lithiumphenyl-m-methyl ether and reacting this with N-methyl acridone, thecompound produced.

is Q-(m-methoxyphenyl) 7 .methyl acridane chloride.

The above compounds are unique in that their solutions have a lowsurface tension and other favorabl properties with in agar disc platesgive wide zones of bacterial inhibition.

At times it is difficult to purify the above mentioned acridane-mineralacid salts of the invention. Frequently repeated recrystallizationresults in no improvement of purity since it only accomplishes furtherdecomposition. It has been found to be exceedingly advantageous toproduce the corresponding 9-alkoxy acridane as an interr absolutemethanol.

14 mediate for purification. These compound are easily purified and arean excellent source for obtaining pure acridane-mineral acid anionsalts. The 9-alkoxy acridane derivative may be prepared as indicatedabove by adding an excess of alkali to a solution of theacridane-mineral acid anion salt to produce the acridolw By simplywarming the acridol formed with an alcohol, the corresponding 9-alkoxyacridane is obtained. Investigation shows that the methoxyl derivativeobtained by refluxing with methyl alcohol are the most desirable 9-alkoxy acridane compounds. The following examples-illustrate thepreparation of the 9-aoridols and 9-alkoxy acridanes.

EXAMPLE XVII 9- (p-hemoxyphenyl) -9-methoxy-1 O-methyl acridane Anaqueous solution of 9-(p-hexoxyphenyD- IO-methyl acridane chloride (seeExample II) or the bisulphate (see Example III) or a bromide (seeExample IV) is covered with ether and treated with a dilute solution ofalkali. The ether layer is separated, washed free of alkali and driedover anhydrous magnesium sulphate and adsorbing charcoal. The solutionis filtered and concentrated to a residue. The residue is dissolved inn-hexane, the solution evaporated to a small volume. On cooling, thecompound 9-(p-hexoxyphenyl)-10-methyl 9acridol crystallizes from thesolution having a melting point of C.

The above mentioned acridol is refluxed in On cooling, the compound 9-(p-hexoxyphenyl) -9-methoxy-1 0-methyl aeridane crystallizes out, isfiltered, washed with methanol and dried in vacuum at 50 C. Thiscompound has a melting point of '77-'78" C.

EXAMPLE XVIII 9- (p-methoxyphenyl) -9-methoa:y-10-phenyl acridane"Treatment of the above mentioned acridol with methanol yields thecompound Q-(p-methoxyphenyl)-9-methoxy-10-phenyl acridane, having amelting point of 1585-1605 C.

, IEXAMPLEIUX 9- (o-methox-yphenyl) -9-methorry-10methyl acridaneFollowing the procedure of Example XVII but using 9- (o-methoxyphenyl)10-methyl-acridane chloride, (see Example VI), the compound 9-(0-methoxyphenyl) -l0-methyl-9-acridol is obtained upon alkali treatment.This compound has a melting point of 132-135" C.

The treatment of the above acridol with methanol yields9-(o-methoxyphenyl) -9-methoxy-l0- methyl acridane, having a meltingpoint of 162- 163 C. with decomposition.

EXAMPLE XX 9- (p-n-butomyphenyl) -9-methowy-10-methyl acridane EXAMPLEXXI 9- (p-n-hewowyphenyl) -9-methomy-10-ethyl acridane (I)CeH1a O CH:

By following the procedure of Example XVII starting with the compoundQ-(p-n-hexoxyphenyl)-10-ethyl acridane chloride (see Example VIII), thecompound Q-(p-n-hexoxyphenyl) -10 ethy1-9-acrid01 is prepared upontreatment with alkali. The refluxing of this acridol compound withmethanol produces the compound 9-(p-nhexoxyphenyl) -9-methoxy-10-ethylacridane.

EXAMPLE XXII 9- (p-n-hexozcyphenyl) -9-methoxy-10-benzyl acridane OOH;

By following the procedure of Example XVII but starting with9-(p-n-hexoxyphenyl)-l0-benzyl acridane chloride (see Example IX), thecompound Q-(p-n-hexoxyphenyl) -10-benzyl-9-acri dol is prepared upontreatment with alkali. This compound has a melting point of 126.5128.5C. Refluxing of this-acridol compound with methanol produces thecompound Q-(p-n-hexoxyphenyl) -9-methoxy-10benzyl acridane, having amelting point of 1l8.5-'l20.5 0.

EXAMPLE XXIII 9- (p-n-octylowyphenyl) -9-methoacy-1 O-methyl acridane OCBH17I1 1 I CH5 By following the procedure of Example XVII but startingwith 9-(p-n-octyloxyphenyl) -l0- methyl acridane chloride (see ExampleX), the compound 9-(p-n-octyloxyphenyl) -l0-methyl-9- acridol isobtained on treatment with alkali. This acridol upon refluxing withmethanol is converted to the compound Q-(p-n-octyloxyphenyl)Q-methcxy-lO-methyl acridane, which has a melting point of 7275 0.

EXAMPLE XIHV 9- (ZJ-Z-ethyZbutOxyphenyZ) -9-methoacy-10- methyl acridaneC] CzH fiy proceeding" according to Example XVII. but starting with9-(2eethylbutoxyphenyl) -10- methyl acridane chloride (see Example XI),the compound 9-(2-ethylbutoxyphenyl) -10 methyl 9- acridol is preparedupon treatment with alkali. Upon refluxing this acridol with methanol,the compound 9- (p-2-ethylbutoxyphenyl) -9-methoxy-lO-methyl acridane isprepared.

EXAMPLE XXV 2,9 methoxy 9 (p n hexoxyphenyl) 10- methyl acridane O-CoHn-By following the processv of Example XVII but starting with2-methoxy-9-(p-n-hexoxyphenyl) IO-methyl acridane chloride (see ExampleXIII), the compound 2 methoxy 9 -.(p n hexoxyphenyl)-10-methyl-9-acridol is obtained upon treatment with alkali. Uponrefluxing this acridol with methanol the compound 2,9-methoxy-9-(p-n-hexoxyphenyl) -10-methyl acridane is formed.

EXAMPLE XXVI 1 chloro 9 memory-9-(p-n-hemomyphenyl)- 4,10-dimethylacridane ?CoHuperature.

EXAMPLE XXVII 9 (p n decyloxyphenyl) 9- methoazy 10- methyl acridane(!)--Cm-H211 By following the procedure of Example XVII but startingwith 9-(p-n-decyloxypheny1)-l0e methyl acridane chloride (see ExampleXII), the compound 9- (p-n-decyloxyphenyl) -.lO-methyl-9- acridol isobtained. Upon refluxing this acridol with methanol the compoundQ-(p-n-decyloxyphenyl) 9 methoxy 10 methyl acridane is formed.

The N -alkyl acridones may be prepared as indicated in Examples IA, IBand IC, for example, the N-methyl-Z-methoxy-acridone may be prepared byreacting Z-methoxy acridine with dimethyl sulfate.4,10-dimethyl-l-chloro-acridone may be prepared by reactingl-chlorol-methyl acridine with dimethyl sulphate.

As examples of other Q-acridol compounds and 9-methoxy derivatives whichmay be prepared are 9-(p-n-hexoxyphenyl)-10-n-decyl-9-acridol, 9 (pmethoxyphenyl)-9-methoxy-l0-n-decyl acridane, 9 (p ntetradecyloxyphenyl) 10- methyl 9 acridol and 9 (p ntetradecyloxyphenyl) -9-methoxy-10-methyl acridane.

Also, by replacing the methanol used for converting the acridols to thecorresponding 9-alkoxy derivatives with other alcohols, ethers of otheralkyl groups may be prepared. For example by refluxingQ-(p-n-hexoxyphenyl) 10 methyl- Q-acridol with ethanol,9-(p-n-hexoxyphenyl) 9-ethoxy-10-methyl acridane; with I n-butanol, 9(p-n-hexoxyphenyl)-9-n-butoxy l0 methyl acridane.

To emphasize the totally unexpected antiseptic properties exhibited byrepresentative compounds of this invention, the following table ofcompara tive values is given: a

g fig figs Bacteriostatic Acrifiavin 1 1, 000 1:33, 000 Rivanol(2cthoxy-6,9-dia1nino acridane 1:5, 000 9-(p-n-Butoiwphenyl)-l0-methylacridane chloride. 1:50, 000 1:1, 500, 000Q-(p-n-Hexoxyphenyl)-10-methy1 ac- 'ridane chloride 1:100, 000 1:5, 000,000 9(p-n-Hexoxypheny1)-l0-benzyl acridane chloride 1:100, 000 1 4, 000,000 Q-(p-n-Hexoxyphenyl)-lO-ethyl acridane chloride 1:50, 000 1:10, 000,000 9 (p-n-2-Ethylbutoxyphenyl) 10 methyl acridane chloride; 1:50, 0001:6, 000, 000 Q-(p-n-Octoxyphenyl) -lO-methyl acridane chloride I 1:100, 000 1:4, 000, 000 9 (p-n-DecyloxyphenyD-lflmethyl acridanc chloride1; 100, 000 1:10, O00, O00 Q-(p-n-Hexoxyphenyl) 10 thyl acridanebisulfate 1:10, 000, 000

The term bactericidal refers to the maximum dilution which will kill aculture of Staphylococcus aureus in five minutes. Bacteriostatici refersto the maximum dilution which will prevent the growth of theabovementioned organism.

Both tests are made by the oflicial methods of ing powders, toothpastes, etc.

Due to the highly antiseptic properties and low toxicities of thecompounds described, these preparation have many and varied applicationsin preventing and .duringbacterial infections.

As illustrative examples of the preparations referred to above are thefollowing:

EXAMPLE XXVIII The water soluble salts of the invention form,

Stable aqueous solutions and :arei'efiective as germicides even in verydilute solutions,=while by practicing further dilution these solutionsretain bacteriostatic action. As usedin' this. specifica- .tionzthe termantiseptic refers to a substance which. prevents or arrests the" growthof microorganisms either by inhibiting theirzactivitymr destroying them.The word germicide.;.refers to. an agent which destroys microorganisms.

EXAMPLE ")QKIX ..I have determinedafter a thorough investigation thataqueous solutionsin 1: 1,000 concentration are very desirableforpractical use. "Such a solution may be prepared by dissolving 1 unit byweight of the acridane antiseptic in 1,000 units of distilled water.

-,A-suitable tincture using: one of thesehalides may beprepa-redasfollows:

0.1 gm. Q-(p-n-hexoxyphenyl)- methyl acridane chloride 54.0 cc. ethylalcohol denatured 5.0 cc. acetone 41 cc. distilled water "Other acridanehalides may be used in place. of

the acridane compound used here.

EXAMPLE XXXI The antiseptic compounds disclosed .herein may be made upfor use in tooth pastes'or powder form byembodying about 0.1% of theactive ingredient ina conventional tooth paste or powder base.

EXAMPLEXXXII A dusting powder maytbej prepared by incorporating about 1%of the antiseptic compounds of theinvention into a therapeutically inert.fine

powder.

application is continuation-.finepartzof my --earlier'-application,Serial Number 781,758, filed October 23, 1947, now abandoned.

The present application; isdi-rectedito' applicants novel antiseptic.mineral-anion acridane compounds. Applicants copending application-Serial.No. 191,088 of October'l9,1950;-which?'is a division of thepresent application, is directed to applicants novel 9+alkoxyracridane:compounds. These compounds .are intermediates for and derivatives ofthe compounds of. the present application. Applicants novel acridol-:.compounds are the subject matter. of..applicants.copending.application. Serial No. 250,185 ,1 filedl'Ootober 6, 1951, which is adivisional application .of the present application.

Others may readily 'adaptzthe invention: for use under variousconditionsoflservice, byxemploying one or moreof vthenovel features-disclosed herein, .or equivalents thereof. iAS :at present advised withrespect ;.to the apparent scope of my invention, .I:desire1to;claim:thefollowing subject'matter.

.Iclaim:

,1. An *acridane compound characterized -by the presence of an.alkoxyephenyl;groupaati the 9-.position' and axhydrocarbon group.;.atthexlO- position, the alkylygroup .of said .alkoxyrgroup containing fromoneto fourteen carbon atoms and the hydrocarbon group at' the10-position containing from one -toten carbon atoms.

.-.2.ZSub'stituted :acridane compounds :1 retire sented bytheifollowingformula:

' ethylacridanechloride'.

'6; The-compound 9'(o'ctoxyph'enyl) -'10=methyl acridane chloride.

The compound 9-"(p'=n=dec'yloxyphenyl) =10- methyracridane chloride.

1 8. The processbf preparing" an" acridane'compound of claim1,"which-'"comprises' reacting'an acridone compound with the lithiummetal' derivatives of alkoxybenzene.

' 9..'.'The processeofupreparingn compound-represented by theformula:

WhereinR is an alkyl group containing from one toyfourteen' carbonatoms'inclu'sive'fX 'is' a monovalent radicals elected" from the classconsisting of 'hydrogen," halogen, alkyl and alkoxyfgroups; Y.is ahydrocarbon'group containing frompne to ten "carbonatoms'inclusiverand'iz is a mineral acid -anion, "which'comprisesrreacting the lithium -metal derivativeiof alkoxy benzene"with ,"a "Y N subs'tituted iacridone; and then treating the resultingacrid'ol "with mineral acid. 10."The processbf preparing a "compoundrepresented-by the formula:

Von

is a hydrocarbon group, containingfroinone to ten carbon atomsinclusive, and Z is a mineral acid anion, which comprises: reacting the,9,a lkoxy derivative with a mineral acid.

11. The process of preparing a compound represented by the formula:

wherein R is an alkyl group containing from one to fourteen carbon atomsinclusive, X is a monovalent radical selected from the class consistingof hydrogen, halogen, alkyl and alkoxy groups; Y is a hydrocarbon groupcontaining from one to ten carbon atoms inclusive, and Z is a halide,which comprises: reacting the 9-alkoxy derivative with gaseous hydrogenhalide. E

12. The process of preparing a compound represented by the formula:

groups; Y is a hydrocarbon group containing from one to ten carbon atomsinclusive, which comprises: reacting the Q-alkoxy derivative withgaseous hydrogen chloride.

13. A composition of 'mouor xorois og action antagonistic tomicroorganisms and comprising as an active ingredient a9-alkoxy-phenyl-10- hydrocarbon substituted acridane mineral acid anionsalt; said ingredient being present in combination with a pharmaceuticalcarrier.

14. An antiseptic dusting powder comprising a therapeutically inertpowder in combination with a compound according to claim 2. v

15. An antiseptic composition of matter comprising a solution containingas an active ingredient a compound according to claim 2.

16. A composition according'to claim 15 in the form of a tincture. 1

1'7. The process of preparing the compound represented by the formula: vv

wherein R is an alkyl group containing from one to'fourteen carbon atomsinclusive; X is a monovalent radical selected from the class consistingof hydrogen, halogen, alkyl, and alkoxy groups; Y is a hydrocarbon groupcontaining from one to ten carbon atoms inclusive, and Z is a mineralacid anion, which comprises; reacting an acridol compound of theformulazl OH I/ C with a mineral acid.

18. The process of preparing a compound represented by the formulawherein R is an alkyl group containing from one to fourteen carbon atomsinclusive, X is a monovalent radical selected from the class consistingof hydrogen, halogen, alkyl, andalkoxy groups;

Y is a hydrocarbon group containing fromone to ten carbon atomsinclusive, and Z is an ion selected from the class consisting ofchlorine,

bromine, and iodine, which comprisesyresicting an acridol compound ofthe formula:

r ,with a gaseous hydrogen halide.

wherein R is an alkyl group containing from one to fourteen carbon atomsinclusive, X is a monovalent radical selected from the class consistingof hydrogen, halogen, alkyl, and alkoxy groups; Y is a hydrocarbon groupcontaining from one to ten carbon atoms inclusive, which comprises;

reactina'ri acri'dol: compound: of the following f formula-i withgaseous hydrogen chloride.

20. The process of preparing a compound represented by the formula:

1 a i Y Z wherein R is an alkyl group containing from one to fourteencarbon atoms inclusive, X is a monovalent radical selected from theclass consisting of hydrogen, halogen, alkyl and alkoxy groups; Y is ahydrocarbon group containing from one toten carbon-atoms inclusive, andZ isa mineral acid-anion, which comprises: reacting the "lithium'rme'talderivative of an alkoxy benzene with a Y-N-substitutedacridone; warming-the product I in whichziisamineral'acidanion from the'group consistingor monoland-polyvalentanions.

232*"A communa -representedb the formula in which Z is a mineral acidanion from the group consisting of -mono and polyvalent anions.

241* A compound represented by: the formula N V LE3 in which R is analkyl group containing from one to 14 carbon atoms inclusive.

Within an alkan'ol and-- treating the l resulting compound with'amineralacid.

21 Theprocessof preparing. a compound rep-rresentedby the-formula:

wherein R is an alkyl groupcontaining from one to fourteen carbon atomsinclusive, X is a monovalent radical selected from the class consisting;

of-hydrogen; halogen; alkyl and alkoxy groups;

Y is a hydrocarbon group containing .from' one-to 25. A compoundrepresented by the formula in whichRis-analkyl group'containingfrom'one' in which R is an alkyl group containing'frombne Jto"14*carhoxratomsinclusive:

27. A compound representedbythefoririula O-CaH13 25 in which Y is ahydrocarbon group containing from one to ten carbon atoms inclusive.

28. An antiseptic composition comprising an aqueous solution of a9-alkoxy phenyl-lO-hydrocarbon substituted acridane mineral acid salt.

DONALEE L. TABERN.

to 1945 (J. W. Edwards; Ann Arbor, Michigan; 10

1946.) volume II, part I, page 585.

Beilstein: Handbuch der organischen'Chemie (4th edition, 1935), pages335 and 336, volume 21.

Luttringhaus: Berichte, volume 67, pages 1602 to 1603 (1934).

Wittig et a1.: Berichte, volume 68, pages 924 to 927 (1935).

Frankel: Die Arzneimittel-Synthese, 16th edition, Berlin, J. Springer,pages 640 to 644.

1. AN ACRIDANE COMPOUND CHARACTERIZED BY THE PRESENCE OF ANALKOXY-PHENYL GROUP AT THE 9-POSITION AND A HYDROCARBON GROUP AT THE10POSITION, THE ALKYL GROUP OF SAID ALKOXY GROUP CONTAINING FROM ONE TOFOURTEEN CARBON ATOMS AND THE HYDROCARBON GROUP AT THE 10-POSITIONCONTAINING FROM ONE TO TEN CARBON ATOMS.